Master regulators of unexplained variation in disease risk

疾病风险无法解释的变异的主要调节因素

• 批准号: 10273583
• 负责人: JOSEPH H. NADEAU
• 金额: $ 191.32万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10273583
• 关键词: Address; Animal Model; Architecture; Area; Atlases; Biological; Biological Models; Biomedical Research; Catalogs; Chromosomes; Communities; Complex; Data; Databases; Development; Diagnosis; Diagnostic; Dimensions; Disease; Diseases in Twins; Elderly; Environment; Epigenetic Process; Etiology; Gene Activation; Gene Expression; Gene Silencing; Genetic; Genome; Genotype; Heterogeneity; Human; Human Genetics; Inbreeding; Individual; International; Knowledge; Lead; Link; Mainstreaming; Measures; Medicine; Metabolic; Methods; Molecular; Monozygotic twins; Mouse Strains; Mus; Neurologic; Organism; Outcome; Phenotype; Phylogenetic Analysis; Physiological; Population Analysis; Precision Medicine Initiative; Process; Property; Protocols documentation; Quantitative Trait Loci; Regulator Genes; Reporting; Science; Seminal; Standardization; Surveys; Testing; Therapeutic Intervention; Variant; Vertebrates; Work; biological systems; cohort; data resource; disease heterogeneity; disorder risk; driving force; genome-wide; human disease; innovation; insight; interest; non-Gaussian model; non-genetic; precision medicine; trait

PROJECT SUMMARY Precision medicine requires an understanding of the origins and molecular control over complex traits and disease. The field is largely driven by human genetics, which adheres to a 1918 dogma that phenotype is determined solely by genetics and the environment. Yet, evidence from monozygotic twins and isogenic animal models indicate that up to 50% of phenotypic variation across diverse physiological traits and diseases cannot be explained by genetics or environment – there is something `more' that is unique to each individual, and that cannot be determined by analyzing population-level mean effects. These findings also indicate that even if we did have `complete' genetic and environmental knowledge, a substantial portion of disease heterogeneity would remain unaccounted for. The operating hypothesis for this project is that a substantial fraction of unexplained disease heterogeneity reflects inherently probabilistic properties of the biological system that lead to fixed, deterministic, real biological variation. There is compelling evidence for an evolved molecular circuitry that controls phenotypic variability as a quantitative trait. Thus, understanding variability as a quantitative trait is essential to understanding the etiology of phenotypic diversity (in general) and an individual's disease potential (in particular). Here, we will begin to finally answer the precision medicine questions of: what is the normal or expected disease potential for me? And, what are the origins and regulatory controls of non-genetic, non- environmental phenotypic and disease variability in humans? The first steps towards addressing these questions and identifying mechanisms through which probabilistic processes lead to disease heterogeneity is to create a catalogue of putative variance regulators and genes; a phenotypic, epigenetic, and cellular variance atlas charting the landscape of probabilistic variation in an isogenic model system (mice); and, to demonstrate that the regulatory architecture of variance control is conserved between mouse and humans. If it is true that a significant portion of unexplained disease heterogeneity is due to the molecular control of variability itself, then we will have uncovered an entirely new area of disease etiology that can be harnessed by the community to develop fundamentally new predictive, diagnostic, and therapeutic interventions, irrespective of the disease of interest.

项目摘要 精密医学需要了解对复杂性状的起源和分子控制， 疾病。该领域在很大程度上是由人类遗传学驱动的，人类遗传学遵守1918年的教条，表型是 仅由遗传学和环境决定。然而，来自单卵双胞胎和同源动物的证据 模型表明，跨潜水员物理特征和疾病的表型变异的最多50％不能 可以用遗传学或环境来解释 - 每个人都独有的“更多”， 不能通过分析人口级的平均效应来确定。这些发现也表明，即使我们 确实有“完全”的遗传和环境知识，大部分疾病异质性将 保持不当。该项目的运行假设是大量无法解释的 疾病异质性反映了生物系统的固有概率特性，导致固定， 确定性，实际生物学变异。有令人信服的证据证明了进化的分子回路 控制表型变异性作为定量性状。那就是将可变性理解为定量性状 了解表型多样性的病因至关重要（通常） （尤其）。在这里，我们将最终开始回答以下的精确医学问题：什么是正常或 对我的预期疾病潜力？而且，非基因，非 - 的起源和调节控制是什么 人类的环境表型和疾病变异性？解决这些问题的第一步 并确定概率过程导致疾病异质性的机制是创建一个 推定方差调节因子和基因的目录；表型，表观遗传和细胞方差图集 绘制Isogenic模型系统（小鼠）中概率变化的景观；并且，证明 方差控制的调节结构在小鼠和人类之间保存。如果是真的 无法解释的疾病异质性的显着部分是由于分子控制可变性本身，然后 我们将发现一个全新的疾病病因领域，社区可以利用 从根本上发展新的预测性，诊断性和治疗性干预措施，无论疾病 兴趣。